This invention relates to novel imaging agents for positron emission tomography (PET) and, more specifically, to novel lipid-soluble gallium complexes which should possess utility as myocardial imaging agents.
Positron emission tomography (PET) is a technique whereby a three-dimensional reconstruction of in vivo radionuclide distribution is possible, providing images that map and quantitate tissue activity levels. The demand for new and novel positron-emitting radiopharmaceuticals continues to increase as more institutions acquire instrumentation for PET imaging.
There are two gallium radioisotopes, Ga-67 and Ga-68. Both of these gallium radioisotopes possess nuclear properties that make them attractive for use in nuclear medicine. The first, Ga-67, is cyclotron-produced and is commercially available as gallium chloride and gallium citrate. The second, Ga-68, has the distinction of being one of the few short-lived positron emitting radionuclides available from a parent/daughter generator system. The Ge-68/Ga-68 generator is commercially available and is attractive because of its relatively long parent half-life (287 days) and convenient daughter half-life (68 min.). The generator-based radiopharmaceuticals may provide a useful and effective way of PET imaging without an on-site cyclotron.
Numerous gallium-68 radiopharmaceuticals have been reported, and some are in routine use for human studies. Unfortunately, development of lipophilic gallium-68 tracers for perfusion imaging of the brain and heart has not been successful. There are tris(salicylaldimine) complexes of gallium that might be used for evaluation of myocardial perfusion. (Green, M. A. and Welch, M. J.: Synthesis and crystallographic haractyerization of a gallium salicylaldimine complex of radiopharmaceutical interest. J. Am. Chem. Soc. 106:3689, 1984; Green, M. A., Welch, M. J., Mathias, C. J., et al: Gallium-68 1,1,1-tris (5-methoxysalicylaldimino-methyl)ethane: A potential tracer for evaluation of myocardial blood flow. J. Nucl. Med. 26:170-180, 1985; Green, M. A.: Synthesis and biodistribution of a series of lipophilic gallium-67 tris(salicylaldimine) complexes. J. Labeled Compounds Radiopharm 23:1221-1222, 1986). However, these agents proved to be unsuitable for clinical use as myocardial perfusion imaging agents because they behave neither as freely diffusible tracers nor as microsphere analogs. Neutral and highly lipid soluble Ga-LICAM complexes have been reported. (Moerlein, S. M., Welch, M. J., Raymond, K. N.: Use of tricate cholamine legends to alter the biodistribution of gallium-67. J Nucl. Med. 23:501-506, 1982). These complexes showed little brain uptake, which suggests that lipid-solubility is not the sole requirement for molecules to penetrate the intact blood-brain barrier. No gallium tracers have been developed that effectively cross the barrier for cerebral blood flow studies.
Despite its short half-life, 75 seconds, the Rb-82, produced by a Sr-82/Rb-82 generator, is quite useful for assessment of myocardial perfusion. (Goldstein, R. A., Mullani, N. A., Wong, W. H., et al: Positron imaging of myocardial infarction with rubidium-82. J. Nucl. Med. 27:1824-1829, 1986; Gould, K. L., Goldstein, R. A., Mullani, N. A.: Economic analysis of clinical positron emission tomography of the heart with rubidium-82. J. Nucl. Med., 30:707-717, 1989). The generator produced agent can support clinical cardiac PET imaging without an on-site cyclotron. A comparable Ga-68 compound with a half-life of 68 minutes may provide significant improvements for PET myocardial imaging.
The zinc-62/copper-62 radionuclide generator (Robinson G. D.: Generator systems for positron emitters. In Positron Emission Tomography, Reivich, M., Alavi, A., eds., A R Liss, New York, 1985, pp 81-102; Robinson, G. D., Zielinski, F. W., Lee A. W.: Zn-62/Cu-62 generator: a convenient source of copper-62 radiopharmaceuticals. Int. J. Appl. Radiat. Isotopes 31:111-116, 1980; Thakur, M. L., Nunn, A. D.: Preparation of carrier-free zinc-62 for medical use. Radiochem. Radioanal. Letters 2:301-306, 1969; Ueda, N., Nakamoto, S., Tanaka, Y., et al.: Production of Zn-62 and development of Zn-62/Cu-62 generator system. J. Nucl. Med. 24:P124, 1983) is also a possible source of radiopharmaceuticals for diagnostic imaging by PET in locations that lack an in-hospital cyclotron for radionuclide production. The potential of this generator to provide clinically useful copper-62 radiopharmaceuticals has been reported. (Robinson, G. D., Zielinski, F. W., Lee, A. W.: Zn-62/Cu-62 generator: a convenient source of copper-62 radiopharmaceuticals. Int. J. Appl. Radiat. Isotopes 31:111-116, 1980; Thakur, M.L., Nunn, A.D.: Preparation of carrier-free zinc-62 for medical use. Radiochem. Radioanal. Letters 2:301-306, 1969; Ueda, N., Nakamoto, S., Tanaka, Y., et al.: Production of Zn-62 and development of Zn-62/Cu-62 generator system. J. Nucl. Med. 24:p124, 1983). The principal disadvantages of the Zn-62/Cu-62 generator system are the rather short (9 hour) half-life of the cyclotron-produced parent, which means that the generator is useful for only one to two days. Nonetheless, the clinical potential of a series of copper(II) bisthisemicarbazone complexes, specifically Cu(PTSM), as myocardial and perfusion tracers have been demonstrated. (Green, M. A., Klippenstein, D. L., Tennison, J. R.: Copper (II) bis(thiosemicarbazone) complexes as potential tracers for evaluation of cerebral and myocardial blood flow with PET. J. Nucl. Med. 29:1549-1557, 1989; Green, M. A.: A potential copper radiopharmaceutical for imaging the heart and brain: copper-labeled pyruvaldehyde bis(N4-methylthiosemicarbazone). Nucl. Med. Biol., Int. J. Radiat. Appl. Instrum. Part B 14:59-61, 1989). The Cu(PTSM) is based on an N.sub.2 S.sub.2 ligand and is a neutral and lipid-soluble compound. After an intravenous injection, the compound passes through the cell membrane, including the intact blood-brain barrier. Apparently, the compound decomposes intracellularly after interacting with sulfurhydryl groups. (Baerga, I. D., Maickel, R. P. and Green, M. A.: Subcellular distribution of tissue radiocopper following intravenous administration of [Cu-62]-Cu(PTSM). J. Nucl. Med. 30:920, 1989 (Abstract No. 812). The regional distribution is a reflection of regional perfusion, a property consistent with "chemical microspheres". Therefore, this agent in combination with the Zn-62/Cu-62 generator may provide a convenient source of radiopharmaceuticals for measuring regional blood perfusion of the brain and heart. However, Ga-68 labeled compounds may offer some advantages because the longer half-lives of the parent and daughter may greatly enhance the clinical potential as PET radiopharmaceuticals.
Recent advances in Tc-99 chemistry of complexes based on N.sub.2 S.sub.2 ligands have dramatically enhanced our ability to predict the chemical structure of the final Tc-99m complexes. This series of ligands form strong complexes with (Tc=0).sup.+3. The x-ray crystallography studies of several N.sub.2 S.sub.2 complexes have confirmed the (Tc=0).sup.+3 chemical state and the pyramidal core structure.
The use of N.sub.2 S.sub.2 ligands to investigate the radiochemistry of indium, a plus three cation, has also been investigated. In particular, a unique indium complex, [.sup.113 m In]TE-BAT (tetraethyl-bis-aminoethanethiol) was evaluated, indicating that the complex, when labeled with .sup.111 In, may show promise as a possible tracer for myocardial perfusion imaging. (Liu, B-L, Kung, H. F., Jin, Y. T., Zhu, L., and Meng, M.: A new myocardial imaging agent: synthesis, characterization and biodistribution of [.sup.113m In]TE-BAT. J. Nucl. Med. 30:367-373, 1989).